Staphylococci
Staphylococci are widely disseminated Gram-positive opportunistic bacterial pathogens responsible for many medical problems in humans, including skin and soft-tissue infections, surgical infections, endocarditis and hospital-acquired bacteriemia (Casey et al., 2007; Kloos and Bannerman, 1994). These bacteria are also the cause of several diseases in animals such as birds, cows, dogs, poultries, rabbits and others (Jacques et al., 2010; Pyorala and Taponen, 2009; Stepan et al., 2004). Staphylococci are divided in coagulase-positive species, Staphylococcus aureus (S. aureus) being the most clinically relevant of this group, and coagulase-negative species, such as Staphylococcus epidermidis (S. epidermidis), the most prevalent pathogen associated with infections of implanted medical devices (Vuong and Otto, 2002). The emergence and spread of resistance to multiple antibiotics in staphylococci is now considered a real health treat and impaired therapeutic endeavor to combat these bacteria (Witte et al., 2008).
S. aureus is an opportunistic pathogen that has extraordinary versatility. Diseases caused by this pathogen can affect several hosts, organs and body sites and may become both life threatening as well as chronic (Archer, 1998; Goerke and Wolz, 2004). For example, S. aureus is associated with significant mortality rates in hospitals and increased health costs (Talbot et al., 2006), but is also the most common cause of difficult-to-treat bovine mastitis (Sears and McCarthy, 2003). The ability of S. aureus to cause a broad spectrum of diseases is related to its numerous virulence factors (Archer, 1998) and it is likely that the coordinated or selected expression of specific groups of virulence factors contribute to the development of specific types of infections. For example, the formation of biofilms and the persistence within non-phagocytic host cells seem to facilitate the development of chronic infections by offering the bacterium protection against the host immune system and the action of antibiotics (Alexander and Hudson, 2001; Brouillette et al., 2004; Galli et al., 2007; Stewart, 2002).
Bacterial Small-Colony Variants
Bacterial small-colony variants (SCVs) are derived from normal bacterial strains and show a slow-growth phenotype (i.e., they produce small colonies when cultivated on solid media). S. aureus SCVs are known to form biofilms (Mitchell et al, 2010a; Mitchell et al, 2010b) and persist within non-phagocytic host cells (Sendi and Proctor, 2009). SCVs are bacteria with a dysfunctional oxidative metabolism causing an alteration in the expression of virulence factors, a slow growth and a loss of colony pigmentation (Proctor et al., 2006). This dysfunctional oxidative metabolism causes a decreased susceptibility to aminoglycosides because these antibiotics require the proton-motive force in order to penetrate the bacterium (Bryan and Kwan, 1981). The proton gradient (proton-motive force) normally generated by a functional electron transport chain is also used by the bacterial ATP synthase (also called FOF1-ATPase) to generate ATP (Hong and Pedersen, 2008). In S. aureus, the SCV phenotype results from mutations affecting the electron-transport system and several SCV isolates are auxotrophic for either hemin or menadione, which are needed to synthesize electron-transport system components. SCVs can also be auxotrophic for thiamine because thiamine is required for the biosynthesis of menadione. Other SCVs are no longer able to synthesize thymidine due to mutations in the folate pathway and this also results in a defect in electron transport although the fundamental basis of this is not well understood (Proctor et al., 2006). Some SCVs present yet unknown auxotrophy but still have in common electron transport deficiency which may result, for example, from a defect in the bacterial ATP synthase (Proctor et al., 2006). S. aureus SCVs are isolated from chronic infections, such as lung infections in cystic fibrosis (CF) patients and from osteomyelitis, septic arthritis, bovine mastitis and infection of orthopedic devices (Atalla et al., 2008; Moisan et al., 2006; Proctor et al., 2006). SCVs that are MRSA (methicillin-resistant S. aureus) and multiresistant to several class of antibiotics have also been reported (Vergison et al, 2007). It is now thought that switching from the normal to the SCV phenotype is an integral part of the pathogenesis of S. aureus and that novel therapeutic strategies targeting SCVs are needed to combat infections caused by bacterial species capable of generating electron transport-deficient SCVs (Tuchscherr et al., 2011).
The SCV phenotype is widespread among microbes. SCVs have been described for several bacterial species and have been recovered from many different clinical specimens such as abscesses, blood, bones and joints, the respiratory tract and soft tissues (Proctor et al., 2006). For examples, SCVs were detected among the staphylococci such as Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis and Staphylococcus capitis, among the enteric-disease causing bacteria such as Salmonella serovars, Shigella spp., Escherichia coli and Vibrio cholerae, among the nosocomial pathogens such as Pseudomonas aeruginosa, Burkholderia cepacia, Escherichia coli, Serratia marcescens, Stenotrophomonas maltophilia and Enterococcus faecalis, among the respiratory tract pathogens such as Streptococcus pneumoniae and Corynebacterium spp., among uro-genital pathogens such as Neisseria gonorrhoeae and also in a variety of other species such as Brucella melitensis and Lactobacillus lactophilus (Allegrucci and Sauer, 2008; Melter and Radojevic, 2010; Proctor et al., 2006; Wellinghausen et al., 2009). In most of these cases, the SCV phenotype is consequent to a defect in the electron transport chain either caused by alteration of electron transport proteins, restriction in necessary coenzymes, cofactors or precursors or an overall reduction of some metabolic pathways such as the tricarboxilic cycle that ultimately affect and reduce electron transport (Chatterjee et al., 2007; Proctor et al., 2006).
Cystic Fibrosis
Although cystic fibrosis (CF) is fundamentally a genetic disorder, the majority of patients afflicted by this disease will ultimately succumb from respiratory failure subsequent to chronic bacterial infections (Lyczak et al., 2002). More recent investigations reveal that the CF airways are colonized by complex polymicrobial communities constituted of numerous microorganisms, encompassing more bacterial species than originally thought, and suggest that interactions between these microorganisms influence the course of the disease (Sibley and Surette, 2011). Some focus has been directed toward understanding the outcome of the interactions between P. aeruginosa and S. aureus because they are often co-isolated from the CF airways (Harrison, 2007; Hoffman et al., 2006; Mitchell et al., 2010b). The polymicrobial nature of CF lung infections needs to be considered in the development of novel therapeutic approaches (Sibley et al., 2009; Sibley and Surette, 2011).
Staphylococcus aureus is one of the most common pulmonary pathogens recovered from North American CF patients (Canadian Cystic Fibrosis Foundation, 2007; Cystic Fibrosis Foundation, 2008). While it is well accepted that antibiotic therapy leads to improvement of lung function and may reduce morbidity associated with CF, decisions regarding which antibiotics to use and when to treat remain largely empirical (Lyczak et al., 2002; Parkins and Elborn, 2010). Consequently, many antibiotics are currently used to treat CF patients infected with bacteria, including aminoglycoside antibiotics (Gibson et al., 2003; Lyczak et al., 2002). A major problem encountered by CF patients is the emergence of bacteria resistant to antibiotics. For example, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA), most often multi-resistant to antibiotics (Chambers and Deleo, 2009), is increasing among CF patients (Parkins and Elborn, 2010). MRSA infections have been associated with a decline of lung function in CF patients (Dasenbrook et al., 2010). Recent studies demonstrate the deleterious effect of S. aureus SCVs and of MRSA and Pseudomonas aeruginosa co-infections in CF children and adults, respectively (Hubert et al, 2012; Wolter et al, 2013).
Burn Patients
Gram positive bacteria, mainly staphylococci and MRSA, as well as Pseudomonas aeruginosa cause severe infections or co-infections of burn wounds. Prophylactic and therapeutic antibiotics for burns patients often include aminoglycoside antibiotics (Avni et al, 2010).
Bovine Mastitis
Bovine mastitis is the most frequently occurring and costly disease affecting dairy producers. The transmittable bacterium Staphylococcus aureus, the coagulase-negative staphylococci and also many streptococci (S. agalactiae, S. dysgalactiae, S. uberis and others) are amongst the most common causes of intramammary infections leading to bovine mastitis (Tenhagen et al., 2006) and current antibiotic therapies usually fail to eliminate the infection from dairy herds (Sears, P. M. and K. K. McCarthy, 2003). Both the normal and SCV phenotypes of pathogenic bacteria were recovered from mastitis cases (Atalla et al., 2008).
Infections Caused by Antibiotic-Resistant Bacteria
Infections caused by antibiotic-resistant bacteria represent an overwhelming growing problem both in human and veterinary medicine. One reason explaining this widespread of drug resistances is that the currently available antibiotics have been largely designed on a limited number of chemical scaffolds, which allowed pathogens to adapt and circumvent common antibiotic action mechanisms (Shah, 2005; Talbot et al., 2006).
Foodborne Bacteria and Illnesses
A number of bacterial species such as Listeria spp. and Bacillus spp. can contaminate food and cause infections in humans. To name a few, Listeria monocytogenes, L. ivanovii, and Bacillus cereus can cause listeriosis (Guillet et al, 2010) and food poisoining (Bad Bug Book, FDA). Bacillus subtilis, B. coagulans, B. licheniformis and B. sphaericus are also known to cause illnesses. Bacillus anthracis causes anthrax and can often be acquired by contact with food producing animals and cattle (beef cattle, sheeps, etc.) and this bacterium is also well-known for its endospores that have been used as biological weapons (Beierlein and Anderson, 2011).
It would be highly desirable to identify antibiotic compounds targeting electron transport-deficient microbes (e.g., SCVs) and/or potentiating the growth inhibitory activity of aminoglycosides against pathogenic bacteria (e.g., antibiotic-resistant bacteria and/or those causing chronic and severe infections) and/or reducing bacterial resistance development toward aminoglycosides. It would also be highly desirable to identify antibiotic compounds that can be used to reduce bacterial colonization in food, preserve food or treat infections caused by foodborne pathogens.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.